Spatial navigation requires information about the relationship between current and future positions. The activity of hippocampal neurons appears to reflect such a relationship, representing not only instantaneous position but also the path towards a goal location. However, how the hippocampus obtains information about goal direction is poorly understood. Here we report a prefrontal-thalamic neural circuit that is required for hippocampal representation of routes or trajectories through the environment. Trajectory-dependent firing was observed in medial prefrontal cortex, nucleus reuniens of the thalamus, and CA1 of the hippocampus. Lesions or optogenetic silencing of nucleus reuniens substantially reduced trajectory-dependent CA1 firing. Trajectory-dependent activity was almost absent in CA3, which does not receive nucleus reuniens input. The data identify projections from mPFC, via the nucleus reuniens, as crucial for representation of the future path during goal-directed behavior and point to the thalamus as a key node in networks for long-range communication between cortical regions involved in navigation.Hippocampal place cells are part of an allocentric representation of local space that allows animals to navigate to desired locations 1,2 . Place cells provide accurate information about current location but it has remained unclear how the place-cell map is used for animals to navigate from their current position to a goal position elsewhere in the environment. To implement goal-directed navigation, previous studies have proposed the need for a separate representation of future positions that is somehow brought together with the representation of current location to point the network to the goal [3][4][5] . Such pointers may be expressed in the activity of hippocampal place cells. When rats are engaged in a T-maze-based alternation task, in which they take left or right trajectories on alternating laps, place cells with fields on the stem of the maze fire at different rates on left and right-turn trajectories, without changes in the position of the firing field 6,7 . The dependence on trajectory has both retrospective and prospective components, reflecting both where the animal comes from and where it is going 8 . However, as the animal approaches the decision point at the junction of the maze, the representation becomes more forward-oriented 9 , often with trajectories to upcoming locations embedded into the representation 10,11 , in addition to mere changes in firing rate.The source of trajectory information in place cells has not been identified. Here we used a continuous version of the T-maze alternation task 6 to determine how information about succeeding 2 choices is introduced in hippocampal place-cell activity. We hypothesized that the selection of future trajectories depends on a wider circuit including not only the hippocampus but also structures involved in the evaluation and selection of actions, such as the prefrontal cortex [12][13][14] . Neurons in medial prefrontal cortex (mPFC) do not projec...

NMDA receptors promote neuronal survival but also cause cell degeneration and neuron loss. The mechanisms underlying these opposite effects on neuronal fate are unknown. Whole-genome expression profiling revealed that NMDA receptor signaling is decoded at the genomic level through activation of two distinct, largely nonoverlapping gene-expression programs. The location of the NMDA receptor activated specifies the transcriptional response: synaptic NMDA receptors induce a coordinate upregulation of newly identified pro-survival genes and downregulation of pro-death genes. Extrasynaptic NMDA receptors fail to activate this neuroprotective program, but instead induce expression of Clca1, a putative calcium-activated chloride channel that kills neurons. These results help explain the opposing roles of synaptic and extrasynaptic NMDA receptors on neuronal fate. They also demonstrate that the survival function is implemented in neurons through a multicomponent system of functionally related genes, whose coordinate expression is controlled by specific calcium signal initiation sites.

Current neuromodulation techniques such as optogenetics and deep-brain stimulation are transforming basic and translational neuroscience. These two neuromodulation approaches are, however, invasive since surgical implantation of an optical fiber or wire electrode is required. Here, we have invented a non-invasive magnetogenetics that combines the genetic targeting of a magnetoreceptor with remote magnetic stimulation. The non-invasive activation of neurons was achieved by neuronal expression of an exogenous magnetoreceptor, an iron-sulfur cluster assembly protein 1 (Isca1). In HEK-293 cells and cultured hippocampal neurons expressing this magnetoreceptor, application of an external magnetic field resulted in membrane depolarization and calcium influx in a reproducible and reversible manner, as indicated by the ultrasensitive fluorescent calcium indicator GCaMP6s. Moreover, the magnetogenetic control of neuronal activity might be dependent on the direction of the magnetic field and exhibits on-response and off-response patterns for the external magnetic field applied. The activation of this magnetoreceptor can depolarize neurons and elicit trains of action potentials, which can be triggered repetitively with a remote magnetic field in whole-cell patch-clamp recording. In transgenic Caenorhabditis elegans expressing this magnetoreceptor in myo-3-specific muscle cells or mec-4-specific neurons, application of the external magnetic field triggered muscle contraction and withdrawal behavior of the worms, indicative of magnet-dependent activation of muscle cells and touch receptor neurons, respectively. The advantages of magnetogenetics over optogenetics are its exclusive non-invasive, deep penetration, long-term continuous dosing, unlimited accessibility, spatial uniformity and relative safety. Like optogenetics that has gone through decade-long improvements, magnetogenetics, with continuous modification and maturation, will reshape the current landscape of neuromodulation toolboxes and will have a broad range of applications to basic and translational neuroscience as well as other biological sciences. We envision a new age of magnetogenetics is coming.Electronic supplementary materialThe online version of this article (doi:10.1007/s11434-015-0902-0) contains supplementary material, which is available to authorized users.